γ-Aminobutyric acid (or GABA) is the predominant inhibitory neurotransmitter in the mammalian central nervous system. In the prosencephalon, GABA is mainly synthesised by interneurons which co-ordinate complex neuronal circuits via GABAA and GABAB receptors. The GABAA receptors are ligand-activated chloride channels largely localised to the plasma membrane. Typically, GABAA receptors are made up of five analogous membrane spanning protein subunits that assemble from a reportory of protein subunits α (6 genes): β (3 genes): γ (3 genes) in a ratio of 2:2:1, respectively. It is generally assumed that two identical isoforms of each subunit are incorporated into a particular receptor [Atack J R (2011) Curr Top Med Chem 11: 1203-1214].
Classical benzodiazepine compounds such as diazepam allosterically modulate GABAA receptors by binding to the benzodiazepine (BDZ) site that spans the interface of one of the alpha and the gamma subunit of the receptor. Diazepam as a non-selective positive allosteric modulator (PAM) of GABA action brings about sedative, hypnotic, anxiolytic, anti-convulsant, amnesic, anti-nociceptive and myorelaxant effects.
Knock-in genetic experiments have shown that the α1 subunit is responsible for the sedative actions whilst the α2 and possibly α3 subunits are responsible for the anxiolytic potency of BDZ-site PAMs [Möhler H (2012) Neuropharmacol 62: 42-53]. Compounds behaving as negative allosteric modulators (NAM) at the BDZ-site are also referred to as “inverse agonists”. BDZ-site NAM compounds that have no GABAA isoform selectivity show nootropic properties in preclinical tests. However, major pro-convulsive and anxiogenic effects have prevented further clinical studies from being carried out on these compounds
The biological functions of GABAA receptors containing the α5 subunit have been assessed in genetically altered animals as well as with the aid of BDZ-site modulators that appear to be selective in vitro. Electrophysiological studies show that a tonic inhibitory potential exists in most neocortical pyramidal neurons, and that this potential sets the intrinsic excitability threshold of the cells. Moreover, in prefrontal cortex pyramidal cells but not in hippocampal CA1 pyramidal cells, there is a complementarity between Ih mediated by HCN channels and the GABAA α5 mediated tonic current in regulating neuronal firing. This suggests that GABAA α5 inhibitors will have a much greater impact on pyramidal cell activity in the frontal cortex than in the hippocampus. Behaviourally, gene-deletion or reduction of the number of GABAA α5 receptors is associated with an improvement in cognitive functions. Moreover, treatment with various α5 selective NAMs enhanced cognitive performance in intact rodents as well as in a mouse model of Down's syndrome. In humans, the amnestic effect of acute alcohol consumption was attenuated by an α5 selective BDZ-site NAM.
GABAergic neurotransmission is also fundamentally important for the normal function of the dorsolateral prefrontal cortex. It has been proposed that deficits in working memory in schizophrenic patients might be a consequence of reduced GABAergic control of neural circuits in the dorsolateral prefrontal cortex [Lewis D A et al. (2008) Am. J. Psychiatry. 165: 1585-1593]. At the cellular level, GABAergic chandelier cells regulate the activity of pyramidal neurons via GABAA α2 receptors located at the axon initial segment. This mechanism appears important for the maintenance the optimal synchronization of pyramidal neuron activity at gamma band frequency in the prefrontal cortex. However, a recent report indicated that enhancement of GABAA α2/α3 function may not be sufficient for the improvement of cognitive function [Buchanan R W et al. (2011) Biol. Psych. 69: 442-449]. Indeed, prevailing theories stress the need for hippocampal-prefrontal synchronisation and connectivity for optimal cognitive function [Akbarian S (2008) Am. J. of Psychiatry 165: 1507-1509; Uhlhaas P J et al (2008) Schizophr Bull 34: 927-943].
On the basis of the mechanisms outlined above, simultaneous augmention of GABAergic neurotransmission at GABAA α2 subunits on the axon initial segments of pyramidal cells and attenuation of tonic inhibition by blockade of GABAA α5 receptors in the hippocampus may be predicted to improve the cognitive dysfunction in different disorders such as Alzheimer's disease, Down's syndrome, schizophrenia, Huntington's disease, and dementias of different origin.
There exists a large, unsatisfied need in the treatment of cognitive deficits associated with various age-related disorders, neurodegenerative or vascular disorders as well as schizophrenia. Current treatments for Alzheimer's disease, the pathology with the greatest prevalence, are based either on inhibition of cholinesterase (e.g. donepezil) or on NMDA antagonism (memantine). However, cholinesterase inhibitors have a large number of undesirable effects relating to their mechanism of action, whilst the true efficacy of memantine is limited. Consequently, having new therapies of greater efficacy and better tolerability would be especially valuable.
International patent application WO 2012120206 discloses a family of compounds having the following structure:

These compounds are disclosed to be useful in the treatment or prevention of psychiatric and neurological disorders, as selective ligands for the α5 subunit of the GABAA receptor.